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3. Analysis ofSpontaneous Adverse Event ReportsPotentially Suggestiveof GlucoseDysregulation in

Lilly Clintrace Database

Using the methods described in Section 2.1, atotal of 945 adverseevent reports wereidentifiedin the comprehensive reviewofspontaneous adverse event reportsin the Lilly

Clintracedatabase. Figure 3.1 shows the report flow algorithmby whichthese case

reports were evaluated. As shown inthis figure, ofthese 945 reports:

* 716reports did notmeet criteria as severe cases ofglucose

dysregulation, and were therefore not included in this review

* 38 reports did notmeet other criteria for inclusion in this review ie,

the patient was notreceiving olanzapine, peak glucose


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Summary of Report Categorization and Clinical Assessment of Etiologic Classification of Glucose DysregulationSpontaneous Adverse Event Reports through 31 Mar 02

Clinical Assessmentof I

Classification of Glucose DysregulationL

IndeterminableIN

14

16

0

0

14

30

6

16

Other Apparent Etiology OE

Possible Other Etiology POE

Other Etiology & Olanzapine PossibleOE+OP

Possible Other Etiology & Olanzapine

Possible POEOP

Olanzapine Possible OP

20 Mar 2003No Other Apparent Etiology NOAE

Figure 3.1. Summary of reportcategorization and clinical assessmentof etiologic contributors.

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Does report ha dkfinttiveividneof glucosedysregulationi.e., definitive MedDRAterm, .,

I glucose peak > 126 mg/dl, and/or Clintrace text`ider,tifiifier?

Yes

cases with verified hyperglycemia I diabetesmellitus definitive MedDRA Preferredtern, or

spportive data in Clintrace report

LWasthere rePort of de:t coma and/J

No

Potentiallysevere cases with report of death, coma and/or acidosis

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3.1. Adverse EventReportsNot Meeting Inclusion CriteriaOf the 945 adverseevent reports evaluatedfor this review, 716reports wereidentifiedas

nonsevereie, not involving death, coma, andloracidosis, and thus did notmeet criteria

for inclusion in this review ofsevere adverseevents. Additionalinformationaboutthe

716cases that were outside the scopeof this review is available upon request.

Of the 945 adverse event reports evaluated for this review,another38 reports failed to

meet the criteria for a glucose dysregulationadverseevent for atleast oneofthe

followingreasons:

* The patient was foundnot to be receiving olanzapine atthe onsetof

the reported adverse event;

* The patient was reportedto have apeak glucose


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Table 3.1. Category 0-a: Nota Case - NonsevereAdverse Event ReportThat Did Not Meet Inclusion CriteriaforGlucose Dysregulation n=22

ECase ID MedDRA Preferred Terms

Death

Reportedas

Glucose

MetabolismRelated?

ConcomitantDrugsTemporallyAssociated

with Glucose

Dysregulation, Acidosis,

Pancreatitis and/orWeight Gain

ReportedPre.

Existing

GlucoseDysregulation Comments

I NA EWC000606915 Gestational diabetes NA N U Peak glucose unknown. Weightnot reported.

Gestational diabetes mellitus diagnosed after being off

olanzapine approximately5 months. Diabetes

successfully controlled with dietary measures.

Resolved - off olanzapine-5 months at onset. Pre

existingglucoseregulation status unknown.

2 NA EWCOI0527027 Blood glucoseincreased,Extrapyramidal disorder NEC

NA Risperidone3,8,

Fluoxetine 2,3,5,7,8,9

U Peak glucose 115 mg/dl F; baselinenotreported.

Resolvedon olanzapine, fluoxetineand risperidone;

discontinued due to EPS. Pre-existing glucose

regulation status unknown.

3 NA EWC020230150 Hyperglycaemia NOS

.

NA Clorazepatedipotassium

2,5,8,9,

Lithium2,8,9,

Lormetazepam8,9,Mianserin2,8,9,

Venlafaxine2,5,7,8,9

U Peak glucoseIll mg/dl F on 4 day ofolanzapine

therapy. Pre-existing hypercholesterolemia,

hypertriglyceridemia cholesterol498 mg/dl,

triglycerides1242 mg/dl,and possible obesity with

weight95 kg pre-olanzapine. Smoked2 ppd of

cigarettes. Pre-existing glucose regulation status

unknown.

4 NA GB9701285 IA Blood glucoseincreased,

Hypertension NOS

NA Droperidol 2,9,

Lorazepam 8,9

Y Peak glucose 198 mg/dl priorto start of olanzapine.

Hypertension and hyperglycemiapreceded startof

olanzapine, diagnosedby treating physicianafterolanzapine begun. Outcome unknownon olanzapine.

5 NA GBS99I104697 Diabetesmellitus NOS,

Weight increased

NA Acamprosate,

Buspirone8,9,

Ethinylestradiol/

levonorgestrel2,5,8,9,

Nitrazepam 8,9,

Quetiapine2,7,8,

Sertraline 2,5,7,8,9,

Zopiclone 9

U Peak glucose unknown. Weight gainbegan with onset

ofdiabetes mellitus which occurred6.5 m after

olanzapine discontinuation. History of hypertension.

Pre-existing glucose regulation statusunknown.

Outcomeof eventunknown off olanzapine.

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Table3.1. Category0-a: Nota Case - NonsevereAdverse Event Report That Did Not Meet Inclusion CriteriaforGlucoseDysregulation n=22 continued

Case ID MedDRA Preferred Terms

Death

Reported as

Glucose

MetabolismRelated?

ConcomitantDrugs

TemporallyAssociated

with Glucose



ReportedPre

Existing


6 NA GBS010208276 Blood glucose increased,

Glycosylated haemoglobinincreased

NA Rispendone3,8,


U Peak glucoseunknown. Elevated blood glucose andHbAlcoccurred -3.5 m afterolanzapine was

discontinued;on nsperidone -3.5 monthsat onset. Has

family history of diabetes mellitus. Status of pre

existingglucose regulation unknown. Event notresolved offolanzapine.

7 NA US97083850A Glycosuria present,

Haematuria

NA U U Patient with history of VonHippcl-Lindaudisease,

resected renal cortex tumors and partial nephrectomy.

Peak glucose 116 mg/dl with 2+ glycosuriaand

hematuria approximately6 weeks after starting

olanzapine. Previousurinalysis for glucoseand blood

negative 5 and 8 monthsbeforeevent. Pre-existing

glucoseregulation statusis unknown. Patient was not

known to have diabetesmellitusat time of event.

Weight56.0 kg. Outcomeis unknown, off olanzapine.-

8 NA US97094765A

-

9 AN US98022098A

Hyperglycaemia NOS NA Valproate 1,7,8,9,


Y Peak glucosereported 120 mg/dl at time of event.

Glucose 134 mg/dl 2.5 months before olanzapinestarted. Unknown if patient had diabetes mellitusat

time ofevent. HbAlc not reported. Pre-existing

glucosedysrcgulation reportedas hyperglycemia.Weight andBMI not reported. Event resolvedon

olanzapine.

Blood glucoseincreased,Polydipsia,

Polyuria

NA Thiothixenc 2,9,

Valproate 1,7,8,9,

Paroxetine 2,5,6,7,8,9

U Peak glucose 800 mg/dl after off olanzapine 14 days;

polydipsiaand polyuria onset at unreported time. It

was unknown if patient had pre-existingglucosedysregulation. Weight and HMt not reported. Patienthospitalized at 2 weeks following olanzapine cessation

treated with insulin for 3 weeks. Outcome is improved

offolanzapineand controlled with diet.

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Table3.1. Category 0-a: Not a Case - NonsevereAdverse Event ReportThat Did Not Meet Inclusion CriteriaforGlucose Dysregulation n=22 continued

E CaseID MedDRA PreferredTerms

Death

Reported asGlucose

MetabolismRelated?

ConcomitantDrugsTemporallyAssociatedwith Glucose



ReportedPre

Existing


-

10 NA US980707664 Aggression,Hyperglycaemia NOS,

Weightincreased

NA Paroxetine2,5,6,7,8,9 Y Peak glucose400 mg/dl at 11 days after olanzapine

stoppedbecause psychiatrist thought shedidnot need

it; becamemore aggressiveafter olanzapine stopped.

Pre-existing glucose dysregulation reported with

glucose levels 134 to 149 mg/dl approximately3

months before peak glucose measured. Weightand

height were notreported. It is unknown if the patient

haddiabetes at the time ofevent. Eleven days after

olanzapinewas discontinuedhad a blood glucoselevel

400 mg/dl. Insulin therapy was started. Patient had

weight gain at unspeci liedtime. Outcome of event isunknownoff olanzapine.

11 NA US9811 12 91 1 B lo od glucoseincreased,

Diabetes mellitus NOS,

Lactation disorder NOS,

Weight increased

NA Benztropine 8,

Chlorpromazine 2,9,

Fluphenazine 2,9,

Lorazepam8,9,

Valproate 1,7,8,9

U Peakrandom glucosewas 202 rng/dl after beingoff

olanzapinefor approximately3 months. Weight gain

and lactationdisorderbegan during olanzapine therapy;

BMJ 35 kg/rn2. Glycosylated hemoglobin level was

8.0%on unspecified date. Pre-existing glucoseregulation statusunknown, althoughglipizide was

listed as a concomitant medicationstart date not

reported. Outcome was unknown; patientremained

offolanz.apine.

12 NA US000949426

-

Blood glucoseincreased,

Weightincreased

NA Benztropine 8,

Carbamazepine2,5,7,

Clonazepam8,9,

Glibenclamide,

Magnesium oxide,

Multivitamin,

Phenytoin2,4,8

Y Peak glucose 149 mg/dlon olanzapine. Pre-existing

TypeII diabetes mellitus with glucose 188 mg/dl and

HbAlc6.7% one day priorto beginning olanzapine.

Glucose levels decreasedafter olanzapine started.

Outcomewas improved on olanzapine; glucoseincrease preceded oJanzapineinitiation.

13 NA USOOI 152687 Bloodpressureincreased,

Fluid retention,

Glucose tolerance impaired,

Weight increased

NA Amlodipine 9,

Desipramine2,8,9,

Haloperidol 2,9,

Haloperidol decanoate2,

Lithium2,8,9

U Peak glucoseunknown. "Borderline" diabetes

diagnosed 17m after olanzapinecessation. History of

hypertension,possible obesity 104 kg. Outcomeunknown off olanzapine.

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Table 3.1. Category0-a: Not a Case - Nonsevere Adverse Event Report That Did Not Meet Inclusion CriteriaforGlucoseDysregulation n=22 continued

.

c Case ID MedDRA Preferred Terms

Death

Reportedas

Glucose

MetabolismRelated?

Concomitant Drugs


with Glucose


Pancreatitis and/orWeightGain

ReportedPre

Existing

GlucoseLysregulation Comments

14 NA US001254605

15 NA LJSOO 1254607

-

Body mass indexincreased,

Diabetesmellitus NOS,

Hormone level NOS abnormal,

Hyperlipidaemia NOS,Flypoglycaemia NOS

NA U U Peak glucose 1 19 mg/dl. Concurrent hyperinsulinemia,increasedleptin, hyperlipidemia cholesterol 320 mg/dl

andtriglycerides373 mgIdl. No baseline values

reported. Outcomeand statusof olanzapine useunknown. History ofobesity.

Bodymass index increased,

Diabetes mellitus NOS,1-Iyperlipidaemia NOS,

Hypoglycaemia NOS

NA U U Peak glucose reprintedtobe an "average" of 124mgldl. Concurrent hypennsulinemia,increasedleptin,

hyperlipidemiacholesterol 273 nig/dIand triglycerides

361 mg/dl. Baselinevalues not reported. Outcome

and statusof olanzapine use were unknown.

16 NA USO 10362476 Blood glucoseincreased,Feelingjittery,

Liver function tests NOS abnormal,Porphyrinuria

NA Diazepam 8,9 U Peak glucose unknown. Prior USC of olanzapine,glucoselevelsnotreported. Blood glucoseelevation

occurred14 dayspriorto re-introductionofolanzapine.Urinepositive for porphynns. Outcomeon olanzapineunknown.

17 NA USOI 0565404 Alanine aminotransferase increased,Aspartate aminotransferaseincreased,

Bloodglucoseincreased,

Bloodlactatedehydrogenaseincreased,

Gamma-glutamyltransferaseincreased,Serumfenitin increased,Weight_increased

NA Captopril /hydrochiorothiazide2,5,7,8,

Norlriptyline 8,9

U Peak glucose 124 mgldl F. HbA1 chad normalizedonolanzapinepriorto dietary treatment. History of

hypertension. Peak weight96.8 kg but reportedly notobese. Outcomeresolvedon olanzapine.

18 NA US010769408 Confusion,Bloodglucoseincreased,Peripheral swelling

NA Divalproex 1,7,8,9,Metformin 1,

Risperidone3,8,Humulininsulin

Y Patientbegan taking insulin 8 days priortoolanzapineforblood glucoseof500 mgldl. Patienthad a historyofglucosedysregulationand diabetes mellitus. Patient

was obese, weight 170 kg. Had confusionand

peripheral swelling. Bloodglucose levelsdecreasedto105to 400 mg/dlrange 10 days after startingolanzapineand 19 daysafterstartinginsulin. Event

resolvedon olanzapine; subsequent statusofolanzapincuseis unknown.

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Table 3.1. Category0-a: Nota Case - Nonsevere Adverse Event ReportThat Did Not Meet Inclusion CriteriaforGlucose Dysregu lation n=22 continued

CaseH MedDRA Preferred Terms

Death

ReportedasGlucose

MetabolismRelated?

Concomitant DrugsTemporally AssociatedwithGlucose



ReportedPre

Existing


19 NA US010973487

-

Bloodalkaline phosphataseNOS

increased,

Blood chloride abnormal NOS,

Blood cholesterol increased,

Blood sodiumabnormal NOS,

Blood triglyceridesincreased,

Choiclithiasis,

Gamma-glutamyltransferaseincreased,

Hyperglycaemia NOS,

Platelet countabnormal,

Whiteblood cell Count abnormal NOS

NA Bipenden,

Flunitrazepam8,9,

Haloperidol 2,9,

Haloxazolam8,9,

Trihexyphenidyl,

Zopiclone9

U Patient withelevated GGT6 weeks before starting

olanzapinehad bloodglucose202 mg/dlone monthafter his first and onlydose ofolanzapinc.

Cholelithiasis diagnosed2 daysafter his single

olanzapinedose. Pre-existing glucosedysregulation

andhistory of diabetesmellitus were unknown.

Weight was 76kg and BMI 25 mg/kg2. Patient had

elevatedbloodalkaline phosphatase, cholesterol,

triglycerides,GGT, abnormal NOS bloodchloride,

sodium,platelet count, WBC and one month afterasingleolanzapinedose. Eventresolvedoffolanzapine.

20 NA USOI1075433 Blood glucoseincreased tA U U Patient had fasting glucose 116 mg/dl after having

takenolanzapine for 3 years. Prior status of glucose

regulation unknown. Unknown outcomeon

olanzapinc.-

-

21 NA USOH 176856 Diabetesmcllitus NOS,

Hepatic function abnormal NOS

NA Flunitrazepani 8,9,

Ursodeoxycholicacid

Y Patient with priorhistory ofhyperglycemiaand drug

induced impairedliver function reportedlydue to

halopendol;had worsening hepatic function after

having taken olanzapine for 22 days. Fifty days after

olanzapineand bipenden were stopped, 35 days after

rispendone was stoppedand 70 daysafter

chlorpromazinelphenobarbital/promethazinewas

stopped,she had glycosuriaandelevatedbloodglucose

level. Peak bloodglucoselevel was 153mgldl and

HbAlc 8.2%. Patient had no family history of diabetes

meflitus; weightwas unknown. Eventresolvedoff

olanzapine.

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Table 3.1. Category0-a: Nota Case - Nonsevere Adverse Event Report That Did Not Meet Inclusion Criteria forGlucose Dysregulation n=22 concluded

E-

Case ID

22 NA US020382306

MedDRAPreferred Terms

Death

Reportedas

Glucose

MetabolismRelated?

Concomitant Drugs


with Glucose



ReportedPre

Existing


Bloodcalcium decreased,

Blood glucose increased,

Blood urea decreased,

Glycosylatedhaernoglobin increased,

Haematocrit decreased,

Haemoglobin decreased,

Lymphocytosis,

Neutrophil countabnormal NOS,

Red blood cell countdecreased,

Thrombocytopenia,

White blood cell Countdecreased,

White blood cell count increased

NA Amfebutainone2,9,

Levothyroxine2,

Montelukast

U Patient with history of hypothyroidism, obesity BMI

48kg/rn2, diabetes mellitus and glucosedysregulation

developedsevere thrombocytopenia,decreasedblood

calcium,ureanitrogen, hematocrit, RI3C, WBC,

lymphocytosis,andrandom glucose 115 mg/dl after

havingtaken olanzapinc for morethan2 years. Had

spontaneous nasopharyngealbleed platelet nadir 1K,atypical lymphocytosisand required9 transfusions of

blood bankplateletsin 5 daysbetweenolanzapine

cessation and hyperglycemia; unknown if

corticosteroidsadministered with platelets. Peak

glucose 448 mgldl occurred7 days after olansapine

wasdiscontinued. HisHbAIC was 6.6%.

Hematologic events continue. Outcomeof clevatedblood glucose is notresolvedandelevatedHbAlc is

unknownoffolanzapine for 5 days at eventonset.

Abbreviations:

Concomitant Drugs Temporally Associated with Possible Adverse Events: 1 = Acidosis, Lactic acidosis, Metabolic acidosis; 2 =Diabetes mellitus, Glucosetolerance decreased, Glycosuria,

Hyperglycemia, Insulin requirement changes; 3 = Diabetic Ketoacidosis;4 =Hyperosmolarnon-ketotic coma; 5 =Hyperlipidemia, Hypcrtriglyceridemia;6 = Ketonuria, Ketosis; 7 Pancreatitis;8 Weightloss; 9 = Weightgain; NA =Concomitantslacked temporal association with glucose dysregulation, acidosis, pancreatitisand/or weightgain; N No concomitantsbeing taken;

U = Unknown/not reportedif Concomitantsbeing taken.

DeathReported as GlucoseMetabolism Related? Y = Yes, death reportedas glucosemetabolismrelated; N =No, death reported as due to cause otherthanglucose metabolism; U =Unknown cause

ofdeath; NA = Death notreported.

ReportedPre-Existing GlucoseDysregulationHyperglycemia and/orDiabetes mellitus: Y = Yes, glucose dysregulation precededolanzapine use; N =No, glucose dysregulation did notprecede

olanzapine use; U = Unknownifglucose dysregulation preceded olanzapineuse.

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Table 3.2. Category0-b: Nota Case - Severe Adverse Event Report That Did Not MeetInclusionCriteria fo r Glucose Dysregulation n=16

CaseID MedDRA

PreferredTerms

Death

Reportedas

Glucose

Metabolism

Related?

ConcomitantDrugsTemporally Associated

with Glucose

Dysregulation, Acidosis,Pancreatitis and/or

Weight Gain

Reported Pre

ExistingGlucose

Dysregulation Comments1 2.08 US96110727A Convulsions NOS,Kctoacidosis,

Pulmonary oedema NOS

NA Clonazepam 8,9,

Paroxetine 2,5,6,7,8,9,

Risperidone3,8,Valproate 1,7,8,9

U Peak glucoseunknown. Neitherhyperglycemianordiabetes mellitus reported; not a caseof glucosedysregulation. Ketoacidosisreportedlythought to berelatedto primaryevent of seizuresofunspecified

etiology. Outcome unknown off olanzapine.

2 5.03 US97035185A MetabolicacidosisNOS,Respiratorydistress

NA Diphenhydramine9,

Erythromycin7U Peak glucoseunknown. Neither hyperglycemianor

diabetes mellitus reported; not a case of glucosedysregulation. Admitted to the hospital withmetabolicacidosisand acuterespiratory distress;probable URI

based on concomitantmedications. No clinicalinformation or laboratory valuesreported. Outcome

and status of olanzapine use unknown.

3 4.01 US9709051IA

4 9.01 US9SOIOI42A

Alanine aminotransferase increased,Blood creatinephosphokinaseincreased,Body temperatureincreased,Ketonuna present,

Muscle rigidity,

Protein urine

NA Chlorpromazinc 2,9,Erythromycin7,Lorazepam 8,9

U Peak glucose unknown. Neither hyperglycemianordiabetes mellitus reported; off olanzapine I da y atonset. Not a caseofglucose dysregulation.Concurrentlyhad possible viral infection with fever

peak 39 .2C, trace ketonuria, proteinuria,cogwhcelingand SGPT elevation; arterial pH and

HCO3 not reported. Resolved off olanzapine,chiorpromazine and lorazepam.

Abdominal pain NOS,

Acidosis NOS,Cardio-respiratory arrest,

Nausea,

Vomiting NOS

N Lamivudine 1,2,7,

Stavudine 1,7,Promethazine2,9

U Peak glucoseunknown. Neither hyperglycemianor

diabetes mellitusreported; not a case of glucosedysregulation. Marked obesity BMI 47.0 kg/rn2; HIVpositivein stable condition; had 2 week history ofabdominal pain with increasing nausea and vomitingover2 to 3 days. Diagnosed with refractoryunspecified metabolic acidosis pH


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Table 3.2. Category 0-b: Not a Case -SevereAdverse Event ReportThat Did Not Meet Inclusion CriteriaforGlucose Dysregulation n=16 continued

c. Case II5 6.02 US980707656MedDRA Preferred

Terms

Death

Reported asGlucose

Metabolism

Related?

Concomitant Drugs

Temporally Associated

withGlucose


Pancreatitis and/or

Weight Gain

ReportedPreExisting

Glucose

Dysregulation Comments

Lactic acidosis NA U U Peak glucoseunknown. Neither hyperglycemia nor

diabetes mellitus reported; not a caseof glucose

dysregulation. Reported onlyas having lactic acidosis.

Nolaboratory valuesor clinical history werereported.

Patientreportedlynot hospitalized. Lactic acidosis

improvedoffolanzapine.

6 5.05 US99OI 15843

7 5.06 US990420528

Coma NEC,

Disseminated intravascular coagulation,

Hyperkalaemia,

Hypotension NOS,

Leucocytosis NOS,

Metabolic acidosis NOS,

Pyrexia,

Rhabdomyolysis,

Status epilepticus,

Tachycardia NOS

ConvulsionsNOS,

Depressedlevel of consciousness,

Flyponatraemia,


Pleural effusion,

PneumoniaNOS,Proteinuria present,

Respiratory acidosis,

Respiratory failure exc neonatal

N

NA

Clonazepam 8,9,Levothyroxine2,

Propranolol 2

Albuterol2

U

U

Peak glucoseunknown. Neither hyperglycemianor

diabetes mellitus reported; not a case of glucose

dysregulation. History ofalcohol abuse with5 months

ofsobriety,and obesity. Metabolic acidosis pH6.94

secondary to seizure of 80 minutes duration. Cause of

death was DIC due to metabolicacidosis,

rhabdomyolysisandbr hyperthermia due to seizure.

Seizure reported as possibly due to possible abrupt

clonazepamwithdrawal; following statusepilcpticus

had dilatedpupilsand left lateral gaze deviation.

Autopsyreportedly free of cerebral hemorrhagesand

devoid of reason for seizures; microscopic cardiac

exam showed areas of myocardial necrosis. Onolanzapine, propranolol,levothyroxineand possibly

clonazepamat death.

Peak glucoseunknown. Neitherhyperglycemianor

diabetes mellitus reported; not a case ofglucose

dysregulation. Hadrespiratory failure withrespiratory

andnon-aniongap metabolic acidosis. Concurrent

polysubstanceand alcohol abuse,obtundation,

pneumonia with pleural effusion and seizure; history of

COPDand asthma. Taking phenobarbital; drug level

notreported. Seizure reportedly was `expectedgiven

his history' which included excessive water intake;

serum sodium 115 meqfL and 113 meq/L. Event

resolved off olanzapineand concomitants.

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Table 3.2. Category 0-b: Not a Case - SevereAdverse Event ReportThat Did Not Meet Inclusion Criteria forGlucose Dysregulation n=1 6 continued

Case ID MedDRA

PreferredTerms

Death

Reportedas

Glucose

Metabolism

Related?

Concomitant Drugs


iith Glucose


Pancreatitis and/or

Weight Gain

ReportedPre

Existing

Glucose

Dysregulation Comments8 2.17 US990623621 Ketoacidosis,

Movement disorder NOS,Neuroleptic malignantsyndrome,

Weightdecreased

NA Bupropion2,8,9,

Lcvothyroxine 2

U Neither hyperglycemianordiabetesmellitusreported;

not a case of glucose dysregulation. Diagnosed with

NMS an d ketosis reportedly due to starvation;arterial

pH and HCO3 not reported. BMI 16.9 kg/rn2 following

45 lbs 20.5 kg weightloss whileon olanzapine.

Improvedoffolanzapine.

9 9.02 US990827170 Acidosis NOS,Depressedlevel of consciousness,

Dysarthria,

Miosis,

Mucousmembranedisorder NOS,Overdose NOS,

Pressuresore,

Suicideattempt,Tachycardia NOS

NA NA U Peak glucose unknown. Neither hyperglycemia nor

diabetes mellitusreported. Intentional acute overdosewith trihexyphenidyland olanzapineamount

unknown. Metabolicacidosis withHCO3 1 5 and

anion gap 30. Haddecubiti and CPK elevationat

presentation;had mucous membrane disorder NOS

concurrently. Unknown outcomeand status of

olanzapineuse.

10 2.21 US000540965 Ketoacidosis NA U U Peak glucoseunknown. Neitherhyperglycemianordiabetes mellitus reported; not a case of glucose

dysregulation. MedDRA Preferred Termreported only

as ketoacidosis. Medical history, concomitant

medicationand outcome off olanzapineare unknown.-

11 5.07 USOO1 154063 Apnoea,

Coma NEC,

EncephalopathyNOS,

Hemiplegia,

HypotensionNOS,


Neuroleptic malignantsyndrome,

PneumoniaNOS

NA Ranitidine7 U Peak glucose unknown. Neither hyperglycemia nor

diabetes mellitusreported;not a case ofglucosedysregulation. Hospitalized with respiratory failure ofunspecified etiology, and metabolicacidosis. No pH o r

HCO3 reported. Presented with healingtoe paronychia

withoutcellulitis, respiratory distress with initially

clearlungsand subsequentpneumonia, dehydration

and unresponsiveness. Had fever, diagnosedwith

NMS with labile bloodpressure. lntubated, developed

lateralizing findings withoutpathology on brain MRI;

cultures blood, urine, CSF negative. Developed

pneumonia and left herniplegia before event resolution.

Improvedoff olanzapine.

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Table3.2. Category0-b: Nota Case -SevereAdverse Event ReportThat Did Not Meet Inclusion Criteria forGlucose Dysregulation n=16 continued

.

ECaseID MedDRA Preferred Terms

Death

Reportedas

Glucose

Metabolism

Related?

Concomitant Drugs


with Glucose


Pancreatitis and/or

Weight Gain

ReportedPre

Existing

Glucose

Dregulation Comments

12 4.06 US010666926 AcidosisNOS,Blood creatinineincreased,

Bloodurea increased,

Electrolyte imbalance,

Haematuria,

Ketonuria present,


Polyuna,

Proteinuria present

NA N U Peak glucose unknown. Neither hyperglycemia nor

diabetes mcllitus reported; not acase of glucose

dysregulation. Hospitalization withdiagnosesof

concurrent NMS and fever. Five days after midazolam

stopped,found to havelabile blood pressure, acidosis,

tachycardia, fever, CPK elevation, incontinenceand

tremor; also had proteinuna, ketonuria, andpolyuria.

Thepresenceor absence of glycosuria was not

specified. Outcomeunknown off olanzapine.

13 5.08 USOI 0871462 Hepatic failure,

Leukocytosis NOS,



Pneumoniastaphylococcal,

Renal failure NOS,

Respiratory acidosis,

Respiratory failure cxc neonatal,

Rhabdomyolysis

N U U Peak glucose unknown. Neither hyperglycemia nor

diabetes mellitus reported; not a case of glucose

dysregulation. Hadmetabolic andrespiratory acidosis

pH 7.14. Hadrhabdomyolysis, respiratory, liver, and

renal failure; presentedin month of August with fever,

diaphoresisand unresponsivenesson day of planned

discharge from a group home; CXR showed bibasilar

infiltrateson admission; sputum culture at intubation

grew Staphylococcus aureus. Death due to NMS,

Staphylococcus aureus pneumonia, respiratory,renal

and hepatic failure.

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Table 3.2. Category0-b: Nota Case -SevereAdverse EventReportThat DidNot Meet Inclusion Criteria forGlucoseDysregulationn=16 continued

CaseID MedDRA Preferred Terms

Death

Reportedas

Glucose

Metabolism

Related?

Concomitant Drugs


with Glucose


Pancreatitis and/or

Weight Gain

ReportedPre

Existing

Glucose


14 5.09 USOI1074903 Multi-organ failure, Cardiacarrest,Renal failure NOS, Hyperpyrexia,

Agitation, Suicidal ideation, Hostility,

Anxiety NEC, Judgmentimpaired,Abdominal pain NOS, Constipation,

Difficultyin mictuntion, Insomnia,Blood pressure increased,TachycardiaNOS, Lethargy,Tachypnoea, Coma,

Dry skin, Intentional self-injury,

Whiteblood cell Count increased, Bloodsodiumincreased, Bloodpotassium

increased, Blood chloride increased,

Blood bicarbonatedecreased, Blood ureaincreased, Blood creatinine

phosphokinaseincreased, B'ood calcium

increased, Blood phosphorus increased,

Bloodcreatinephosphokinaseincreased,

Aspartate aminotransferaseincreased,

Bloodalbuminincreased,

Blood urine

present, Protein urine,

Lung infiltration NOS, Prothrombintime prolonged, Metabolic acidosis,

Respiratory acidosis

N Buspirone 8,9,Clomipramine 2,5,9,

Clonazepam8,9,

Fluoxetine hydrochloride2,3,5,7,8,9,

Gabapentin2,8,Haloperidol 2,9,Nortriptyline 8,9,

Zolpidem2,8

U Peak glucoseunknown; neitherhyperglycemianor

diabetes mellitusreported, thereforenot a case of

glucose dysregulaon. Height, weight, 13M1, personal

and family historyof diabetes, baseline laboratoryvaluesnot reported. Patient'sdeath due to multiorgan

failure following fever4 .4C, possible NMS CPK46,040U/L;subsequently 89,000 U/L, musclerigidity and pneumoniapresent after discontinuation of

aB psychotropic medications;had respiratoryandmetabolic acidosis pH 7.26. Diagnosisof pneumoniaand fever followedtreatment witha polypharmacyof

psychotropic medications combinedwithanunspecified formand durationof physical restraint.Laboratory valuesat timeof fever were compatible

with dehydration sodium 156 meq/L,potassium5.0meq/L, chloride 116 meq/L, BUN 49 mg/L, crcatinine2.9 mgfL; fluid intake duringrestraint not reported.

Unknownif hematuna was trauma related. Death 24hoursafterdetection

ofhyperthermia reportedly due to

multi-organ failurepossibly related to dehydrationandmetabolic derangementsdue to possible NMS and/orpneumonia. Unknownif autopsyperformed.

15 1.79 USO11074993 Diabetic ketoacidosis Y Mirtazapine2,8,

Perphenazine 2,9U Peak glucose unknown. No historyof olanzapineuse.

Patientwas not taking olanzapine; was in post-

marketing studyand taking perphenazinc. Height,

weight, BMI, personaland family history, baseline

laboratory values not reported. Patient founddcad athomein bed; causeof death reported as diabetic

ketoacidosis. Blood glucose level, vitreoushumorglucoselevel, pH, HCO3, toxicology reportanddetailedautopsy resultsnot reported.

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Table3.2. Category 0-b: Not a Case -Severe Adverse Event Report That Did Not Meet Inclusion Criteria forGlucose Dysregulationn=16 concluded

ConcomitantDrugs

D ea th T em po ra ll yAssociated

ECaseID MedDRAPreferredTerms

Reported as

Glucose

Metabolism

Related?

with Glucose


Pancreatitis and/or

WeightGain

Reported Pre

Existing

Glucose


16 1.84 US020382427 Blood triglycerides increased,

Diabeticketoacidosis,

Pancreatitis acute

NA Bromperidol 2,9,

Ethyl loflazepate 8,9,

Flunitrazeparn8,9

U Peak glucose778 mg/dl. Patient off olanzapine 17 to

24 daysat eventonset; therefore, this is not a case of

glucosedysregulation on olanzapinc. Risk factors for

development ofdiabetesmellitus includedrace, family

historyof diabetes, obesity BMl 35.9kg/rn2, pre

olanzapine dyslipidemiaand past history of pancreatitis

unreported etiology. Concomitants started and

stoppedsame dates as olanzapine. Elevated

triglycerides 514 mg/dl documented aftertwo weeks

ofolanzapine. Diagnosedwith diabetic ketoacidosis

andacute pancreatitis with arterial pH 6.96, 3+ ketones

in unspecifiedbody fluid, bloodpressure90/60 rnmHg,

respiratoryrate42/mm, amylase 1575 IU/L or 2015

lU/L, lipase 3095 IU/L and HbAlc 13.5%. ACT scan

indicated acutepancreatitis. Abdominal pain occurred

17 daysafter last olanzapinedose; DKA diagnosed24

daysafter olanzapine cessation. Treatment included

intubation, dopamine hydrochloride,insulin and

antibiotics directly into pancreatoduodenal artery.

Triglycerides not reportedat time of presentation with

DKA. Presenceor absence ofinfection as part ofacute

presentation was not specifiedalthoughtreated withantibiotics. Eventsresolved.

Abbreviations:

Concomitant Drugs Temporally Associated with Possible Adverse Events: I = Acidosis, Lactic acidosis, Metabolicacidosis; 2 =Diabetes mellitus, Glucosetolerancedecreased,Glycosuria,

Hyperglycemia, Insulin requirement changes; 3 =Diabetic Ketoacidosis; 4 =Hyperosmolarnon-ketoticcoma; 5 = Hyperlipidemia, Hypertriglyceridemia; 6 = Ketonuria, Ketosis; 7 = Pancreatitis;

8 = Weight loss; 9 = Weight gain; NA =Concomitantslacked temporal association with glucose dysregulation, acidosis, pancreatitis and/or weight gain; N = No concomitantsbeing taken;

U = Unknown/notreportedifconcomitants beingtaken.

Death Reported as GlucoseMetabolismRelated? Y = Yes, deathreportedas glucosemetabolismrelated; N =No, death reportedas due to causeother than glucose metabolism; U = Unknown cause

ofdeath; NA =Deathnotreported.

ReportedPre-ExistingGlucoseDysregulationHyperglycemia and/or Diabetes mellitus: Y = Yes, glucosedysregulation preceded olanzapineuse; N =No, glucosedysrcgulationdid not precede

olanzapine use; U = Unknown ifglucosedysregulation precededolanzapineuse.

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Page 34

3.2. Severe Glucose Dysregulation Adverse EventReportsOf the 945 adverse event reports initially identified in the comprehensive review of

spontaneous adverse event reports in the Lilly Clintrace database, 191 reports were

identified through clinical review as severe adverseevent cases potentially suggestive of

glucosedysregulation and involving death, coma, andlor acidosis. Cases ofparicreatitiswith orwithout reported glucose dysregulation are also presented. Thesecases are

briefly summarized in a tabular format in the following sections, with detailed summaries

foreach case presented in Appendix C.

Theadverseevent reports in the following sections are presented in a hierarchical order

ie, all death cases in Section 3.2.1; all nonfatal coma cases in Section 3.2.2; all nonfatal,

non-comacases involving acidosis in Section3.2.3. A case appears in only one ofthe

three sections according to the priority assigned tothe event death > coma> acidosis.

For example, a fatal case involving acidosis is found in Section 3.2.1, but is not repeated

in Section 3.2.3.

3.2.1. Deaths Category 1

3.2.1.1. Case Tables

A total of48 cases involved death, and metthe criteria for inclusion as a severe adverse

eventpotentially suggestiveofglucose dysregulation temporally associated with

commercially-marketedolanzapine. This number represents allknown cases of death

with a datacutoffof 31 March 2002. Table 3.3 summarizesthese 48 cases designated as

Category 1. Appendix C provides full narratives ofthese cases.

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Table 3.3. Category 1: Cases ofDeath in Which Glucose Dysregulationwas Reported and the Patient Was onOlanzapine at Event Onset n=48

Case HMedDRA Preferred

Terms

Etiologyof

GlucoseDysregulation

Death

Reported asGlucose

MetabolismRelated?


with Glucose

Dysrcgulation, Acidosis,

Pancreatitisand/orWeight Gain

Reported Pre

Existing


1 10.01 CA010503671 Nonketotichypcrglycaemic-

hyperosmolarcoma

POE Y U Y Peak glucose 951 mgldl post-mortem,peripheral blood;

881 mg/dI post mortem vitreous humor. Priortoolanzapine, obesity and fasting hyperglycemia 130

mg/dl present. After6 daysolanzapineuseand

approximately2.5 months of prescribed butuncertain

olanzapineuse, glucoselevel increased further but was

notassesseduntil after death. Reported causeofdeath

was hypcrosmolardiabetic coma and terminal

dehydration. Hada history of street drug and alcohol

abusebut autopsytoxicology negativefor ethanol orother volatile alcohols, cocaine, marijuana, opiates, or

benzodiazepincsand olanzapinepresent 45 nglml

from unspecifiedsample site; patient was reportedly

difficult and noncompliant. ` Elevatedpost-mortem

beta-hydroxybutyratelevelsmay haveresulted from

dehydration. Neitherdetails ofhis `feelingunwell" for

afew days priorto death nor of concomitant

medicationswere provided.

2 12.03 CAOI 0603802 Diabeticcoma NOS POE & OP Y Topiramate 1,2,5,6,7,8,

Valproate 1,7,8,9

U Peak glucoseunknown. Baseline glucoseand medical

details surrounding onset ofdiabeticcoma not reported.

Hadmultiplerisk factors for diabetesmellitusfamily

history, race, obesity. Sixteen-year-oldmale with pie

olanzapineBMI 30.5 kg/rn2developed polyuna,

diabeticcoma and died; unknownif autopsy performed.Patientweighed 250 lb 113.6kg priorto starting

olanzaprne;gained4.5 kg in 3 months during

olanzapinetreatment. Sixmonthspriorto olanzapine

usewas hospitalizedand placedon a "cocktail of

drugs" including "typical antipsychotics."

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Table 3.3. Category 1: Cases ofDeath in Which Glucose Dysregulation was Reported a nd the PatientWasonOlanzapine at Event Onset n=48 continued

;a

- Case ID

3 2.03 EWC980400445

MedDRAPreferred

Terms

Etiologyof

Glucose.

Dysregulation

Death

ReportedasGlucose

Metabolism

Related?


with Glucose


Pancreatitis and/or.

WeightGain

ReportedPre

Existing

Glucose.


Cardiac arrest,

Cardiac failure

NOS,

Hyperglycaemia

NOS,

Ketoacidosis

OE N Haloperidol 2,9,

Lorazepam8,9

Y Peak glucose500 mg/dL. Historyof codeineand

diazepamaddictions causing prior hospitalizations.

Priorto olanzapinepatient had elevated glucose141

mg/dlpp and had received haloperidol. Prcsentcd

with nauseaand leg weakness followedby rigid

abdomen, absent bowel sounds and erysipelas without

culturesof site or blood, or treatmentreported; pH 7.08

with base deficit 23; dehydratedand hypotensive;

treated with dopanlineand dobutamine. Examshowed

responsive, over-mid sizepupils and focal findings

right-sided Babinski with absent oculocephalic

reflexes. Death reported due to cardiac failure and

electromechanical dissociation; iatrogenic

pneumothorax duringcentral line placement treated

withchest tube. Olanzapinelast given on day before

death; unknown status of original concomitantuse.

4 5.02 EWC990202785 Cardiac arrest,

CyanosisNOS,

Dyspnoea NOS,

Hyperglycaemia

NOS,

Hyperkalaemia,HypotensionNOS,

Metabolic acidosis

NOS,

Neuroleptic malignant

syndrome,

Respiratoryfailure

cxcneonatal,

Ventricular

tachycardia

POE N Carbamazepine 2,5,7,

Clomipramine 2,5,9,

Lithium 2,8,9

U Peak glucose1499 mg/dL. The patient presentedwith

hyperglycemiaglucose363 mg/dl; serum glucose

rose to 1499 mg/dl following glucoseadministration,

despite insulin, during resuscitativeattemptsto treat

significant hyperkalemiadue to acidosis pH 7.08

resulting from shock. Type of acidosis was notreported. Etiology of pre-olanzapine weightloss,

lymphadenopathyand hepatosplenomegalynot

reported. Presentation with dyspnea, cyanosis and

hypotension. Pulmonary emboli not reportedat

autopsyafterextensiveresuscitation, norwas sepsis, or

Addisons disease. Deathdue to NMS, hyperkalemia,rhythm disturbances; on olanzapine, clomipramineand

carbamazepine.

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Table3.3. Category 1: Cases of Death in Which GlucoseDysregulationwas Reportedand the Patient Was onOlanzapineat EventOnsetn=48 continued

CaseID

MedDRAPreferred

Terms

Etiologyof

Glucose

Dysregulation

Death

Reported as

Glucose

Metabolism

Related?

Concomitant Drugs


withGlucose


Pancreatitis and/or

Weight Gain

Reported Pre

Existing

Glucose


7 29.03 EWC020230016 Completed suicide,

Hypergycaemia

NOS,

Non-accidental

overdose

IN N Propiomazine maleate

2,9,

Zopiclone 9

U Peak glucose303 mg/dl, femoral blood post-mortem;

resultsobtained post-mortem, five daysafter she had

last been seen. Death was reported as suicide by

intentional overdoseofolanzapineonly; olanzapine

level 0.2 meg/gm, lactate55.2 mmolIL sample site not

reported. Blood was `screened fo r other substances

butonly olanzapinewas detectable." Risk factors for

developing diabetesmellitusincluding height, weight,

personaland family history, baseline laboratoryvalues

were not reported. Inabsence of autopsyinformation,

past medical history and ante-mortem evidenceof

hyperglycemia,unableto confirmglucose

dysregulationas an ante-mortem condition.

8 29.04 FRO2O 100595 Agitation,

Death NOS,

Hyperglycaemia

NOS,

Weightincreased

OE U N U Peak glucose400 mg/dl. Klinefelters syndromewas a

knownrisk factor for diabetes; not obese BMI 20.3

kglm2,but gained weight amount, timingnot

reported. Personaland family history ofdiabetesnot

reported;positivepersonal and family history of

phlebitis. Thirteenmonthsafter starting olanzapine,

patient reported fatigue, and oral candidiasis was found

on exam, HbAlc 9.8%; Ireatmentofcandidiasisand

hyperglycemianot reported. Approximately 3 weekslater, glucoseremained400 mg/dl and acetonepresent

in urine; no treatmentreported. Olanzapine

discontinued three weekslater and 10 daysafter last

olanzapinedose, patient found dead. No autopsy;

causeof death unexplained but suicide or alcohol

ingestion reportedly not suspected. Hyperglycemia

detectedin context of an oral infectionin patient with

Klinefelters syndrome.

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Table 3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reportedand the Patient Was onOlanzapine at Event Onset n=48 continued

Case ID

MedDRAPreferred

Terms

Etiology of

Glucose

Dysregulation

Death

Reported asGlucose

MetabolismRelated?

ConcomitantDrugs


withGlucose


Pancreatitis and/or

Weight Gain

ReportedPre

Existing

Glucose


9 2.06 GBS9909041 38 Arrhythmia NOS,Aspartatc

aminotransferase

increased, Blood

crcatinineincreased,

Bloodurea increased,

Coma NEC,

Diabetesmellitus

NOS, Diarrhoea

NOS, Ketoacidosis,

Left ventricular

failure,

Leftventricular

hypertrophy,

Lethargy, Listless

OE N Alprazolam 8,9,Clonazepam8,9,Lithium 2,8,9,


U Peak glucose 1645 mg/dL. Priorto presentation had 3week history ofpolydipsia,4 days of lethargy, and

diarrhea for 2 days; Consumed -4.5 L soft drinks perday in week prior to death. Cloudy hematuria atautopsy; culture not reported. Death on olanzapine,

paroxetine, lithium, clonazepam and alprazolarn;

autopsy findings includedmassive hepatomegaly,leftventricularhypertrophywith focal myocardial fibrosis,

left ventricular failure,and bloodalcohol 432 mg%.Normokalemiain presence of marked acidosis pH

7.1, left ventricularhypertrophy with focal myocardial

fibrosis and alcohol intoxication were significant

contributors to cardiacarrestand death. Obesity,

dietary non-compliance, sedentary lifestyle, weight

gain and acute alcohol abuse were contributorstohyperglycemiaand acidosis. Pancreaticautolysispresent at autopsy.

10 11.03 G8S010508789

11 2.09 US97022578A

Diabetic

hyperglycaemiccoma

Blood glucose

increased,

Coma NEC,

Death NOS,

IN

POE

Y

N

MetforminI,

Sertraline 2.5,7,8,9

Chlorpromazine 2,9,Lithium2,8,9,

Lorazepam8,9

Y

U

Peak glucoseunknown. Pre-olanzapine Type II

diabetes mellitus and probableobesity female

weighing99.3 kg reportedly died at home in diabetic

coma. Corroborating data, e.g.. vitreous humor glucose

levels and negative findings on toxicologyandanatomy, were not reported. Patient's premorbid

medical status, including history of adherenceto

medications, wa s not reported.

The caselacked detailsaboutthe clinical context in

which DKA peakglucose 900 mg/dl manifestedand

aboutintrinsic risk factorse.g., habitus, race,past

medical history and concurrent diagnoses. TheKetoacidosis,

Pyrexia

etiology of high feverand coma followingresolution of

DKAis notdeterminable from the reported data

beyondthe reportingphysician's suspicion of NMSor

brainstem emboli as cause of death.

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Table 3.3. Category 1: Cases ofDeath in Which Glucose Dysregulation vw --Olanzapine at EventOnset n=48continued

- Case ID

MedDRAPreferred

Ternis

Etiologyof


DeathReported asGlucose

MetabolismRelated?

ConcomitantDrugsTemporallyAssociatedwithGlucoseDysregulation, Acidosis,


ReportedPre

Existing


12 29.05 US97112521 A HyperglycaemiaNOS

POE Y U Ii Peak glucoseunknown. Case lacks details of acuteclinical events; patient had an intrinsicrisk factor

obesity and reportedly undiagnosed diabetes mellituswhich wa s exacerbated. Treatingphysician did notbelieveolanzapinewas responsible for events.

Obesity, undiagnosed diabetesand treating physician

assessment suggest a possible etiology, otherthan

olanzapine exacerbatedthe underlying disease.

Autopsynotperformed; peak glucosenotreported;

death reportedlydue to hyperglycemia.

13 6.01 US97121726A Blood creatinephosphokinase

increased,

Blood glucose

increased,

Body temperatureincreased,

Coma NEC,

Hepatic failure,

HypotensionNOS,

Lactic acidosis,

Nausea,Neuroleptic malignant

syndrome,

Renal failure NOS,

Respiratory failure

cxc neonatal,

Vomiting NOS

POE N Diphenhydramine9,Haloperidol 2,9,

Naproxen 2,7,8,Temazepam8,9

U Peak glucose 1700mgldL. Etiologyofsudden onset ofmarkedhyperglycemia withlactic acidosis, fever42.6C, coma, probablerhabdomyolysis CK 60,000,and multiple organ failure in previously stablepatient

not evident in data. Although NMS was consideredas

adiagnosis, she did not have reported rigidityor EPS

findings. Seizure activity was notwitnessed. Initialsymptoms of nauseaand vomiting may have beenaprimary event or a responseto hyperglycemia and

lactic acidosis. Glycosylated hemoglobin not reported.Blood, urineand CSF cultures were negative; extrinsic

toxins were not discussed. Toxicology studies forprescribed medications,drugsof abuse, or toxins werenotreported. Hada long term seemingly asymptomaticintervalon a complex drug regimenand cataclysmicdecline; autopsynot performed. On olanzapineand

concomitants at death.

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Table 3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported and the Patient WasonOlanzapine at Event Onset n=48continued

i:;.

Case IDMedDRAPreferred

Terms

Etiologyof


Death

Reported asGlucoseMetabolismRelated?

ConcomitantDrugsTemporallyAssociated

with GlucoseDysregulation, Acidosis,


Reported PreExisting

Glucose


14 2.13 US98024165A Gastrointestinalupset,

Ketoacidosis,

Pancreatitis

haemorrhagic,

Pyrexia

POE U Lithium 2,8,9,

Lorazepam 8,9,Valproate 1,7,8,9

U Peak glucose unknown. Presentedwith fever39.4C,flu-like symptoms, and gastrointestinal symptomsNOS; she was not hospitalized. Post-mortem

diagnosisof acute hemorrhagicpancreatitis; therewasno history of alcohol use. Although probablethatthe

patient developedhyperglycemiaduringthe

pancreatitis,neitherglucose levels nor specificreport

ofhyperglycemia or diabetes mellitus was provided,butconservatively assessedas instanceofglucose

dysregulation. It is unknown from the reporteddatawhythe patient was not hospitalizedor furtherevaluated in the 5 daysbetween onset ofsymptomsanddeath. Status of gall bladder function and presenceor

absence ofcholelithiasisatautopsy were not specified;toxicology was notreported.

15 1.33 US98 1012271 Diabeticketoacidosis,

Dry mouth,Speech disorder

NEC,

Thirst,

Visionblurred,

Weight increased

IN Y Buspirone 8,9,Lithium2,8,9,


U Peak glucose867 mg/dL post-mortem vitreoushumor.Risk factors for development of diabetes mellitusincluding obesity BMI 31.9kg/rn2and pre-olanzapine

weightgain with continuedgain on olanzapine. Pasthistory regardingalcohol usenotreported. Toxicology

resultsare compatiblewith the diagnosis ofacute

diabeticketoacidosis. Baseline serum glucoselevelsandclinical information about possible diagnoses

concurrent withacutedeterioration were not reported.

Death occurredon olanzapine, paroxetine,trazodone,lithium, and buspirone; autopsy showed hepatomegalywith fatty metamorphosis,cerebraland pulmonary

vascularcongestion; vitreous humor and bloodacetonelevels = 19 mg/dL and II mg/dL respectively. Causeofdeath was diabetic ketoacidosis.

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Table3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported andth e Patient Was on

Olanzapine at Event Onset n=48 continued

.9

.

Case ID

MedDRAPreferred

Terms

Etiology of

Glucose

Dysregulation

Death

Reported as

Glucose

Metabolism

Related?


with Glucose


Pancreatitis and/or

Weight Gain

Reported Pre

Existing

Glucose


16 12.09 US990420242 Death NOS,Diabeticcoma NOS,HyperglycaemiaNOS,

Hyperphagia,

Malaise,

Polydipsia,

Polyuria

POE N Multiple psychiatric

medicationsNOS

U Peak glucose unknown. Death was reported due to"complications" unrelated to diabetes mellitus.

Reported risk factors for developmentof diabetes

mellitus were age and obesity. She presented with

acuteloss of bladder control and "felt ill." The patients

pre-admissionsymptoms include polyuria, polydipsia

and polyphagia for `some time." Data regarding the

"unrelated complication" which caused death were not

reported.

17 1.36 US9906234 11 Diabetes mellitusNOS,


Mental Status

changes,

Pancreatitis NOS,

Thromboembolism

NOS,

Vomiting NOS

OE N Levothyroxinc 2,

Metformin I

U Peak glucose >400 mg/dl fasting. Hashimotos

thyroiditis, cholelithiasisand obesity by history.Developed vomiting, pancreatitisand heparin-induced

thrombocytopenia duringterminal events. Had

cholclithiasisand suspected panereatitison first

admission after2 yearson olanzapine; when off

olanzapine,and on risperidone glucose increased.

Switchedback to olanzapine and glucose managed with

metformin. Developedconfirmed episode of

pancreatitis with DKA pH 6.9; status of cholelithiasisnot reported. Unknown status of olanzapineandconcomitant use with resolved pancreatitisat time of

death. Developedantibodies to hepann followed bydiffuseclottingafter recovery from the reported

episodeof pancreatitisand DKA.

18 30.06 US990623659 Blood glucoseincreased,

Pancreatitis acute

POE N Valproate 1,7,8,9 U Peak glucose unknown. Onlyreported medical data

werethat patientwas blackand had acute pancreatitisdiagnosed at autopsy, associated withantemortem

elevatedglucose levels, and that panereatitis was thecause of death. Valproate was begun the same month

pancreatitis was diagnosed. The caselacked clinical

detailsnecessary for fully assessingthe patient's risk

factorsand acute medical events. Durationof

olanzapineuse at onset not reported.

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.

-

CaseID

1 9 18 .0 5 US990725729

MedDRAPreferredTerms

Etiologyof

Glucose

Dysregulation

Death

ReportedasGlucose

MetabolismRelated?

Concomitant DrugsTemporallyAssociated

withGlucose


Pancreatitis and/or

Weight Gain

Reported Pre

ExistingGlucose


DiabetesmcllitusNOS,

Loss of

consciousness,

Neuroleptic malignant

syndrome,Renal failure

OE N Fluoxetine 2,3,5,7,8,9 U Peak glucoseunknown. Presentedin July, admitted tohospital and diagnosed with diabetesmellitus after 18monthsof olanzapineuseand 2 years offluoxetine use;

glucoselevels and p1-I not reported. Threedays laterdiagnosed with NMS fever41.7C,rigidity,coma,

CPKpeak 400,000IU. Treatedwith dantroleneand

bromocriptine, CPKand rigidity improvedbutdied due

torenal failure. Autopsy wasnot performed;death

reported due to renal failuredue to probable

rhabdomyolysis.

20 28.01 US991233059 Agitation,

Depression,

Diabeticcomplication

NOS,

Hyperphagia,

Insomnia NEC,

Restlessness,

Urinary incontinence

IN Y Clonazepam 8,9,

Diphenhydramine9,

Fluoxctine 2,3,5,7,8,9,

Glibenclamide,

Metforrnin 1,

Risperidone3,8

Y Peak glucoseunknown. Concurrent insomnia,restlessnessand hyperphagia; diabetes treated with

metformin preceded olanzapine use. Patient'sglycemic

controlat baseline, and during her3-weekhospitalization, were not reported. Obesity BMI 34.2

kg/rn2and age were risk factors for diabetes mellitus.Specific causeofdeathunknown fromavailable data;deathreportedly due to unspecified "diabetic

complications.' Patient was `founddead" at home;

autopsywas not performed. Risperidoneand

diphenhydramine re-started 2 weeksbeforedeath.

21 30.07 US000337604

22 1.46 U5000338270

Blood glucoseincreased,

Pulmonary embolism

POE N Levothyroxine2 U Peak glucoseunknown. The patient'sexcessiveweightandage are possibleetiologies for her hyperglycemicmeasurementsof unreportedseverity. Death was dueto pulmonary embolus at autopsy, not related to

olanzapine administration.DeathNOS,


Renal failure NOS

IN U U U Peak glucose 1299 mg/dL. Concurrentrenal failure;

patientincarceratedatonset. Absenceofclimeal

details,past or concurrenthistory in an incarcerated

patient. Death from unknown cause; unknown status of

olanzapine use at death.-

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Table 3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported a nd the Patient Was onOlanzapine at Event Onset n=48 continued

.8

-

Case ID

23 18.06 US000542556

MedDRAPreferred

Terms

Etiologyof

Glucose

Dysregulation

Death

Reported asGlucose

Metabolism

Related?


with Glucose


Pancreatitis and/or

Weight Gain

Reported Pre

Existing

Glucose


Bloodcholesterol

increased,

Diabetes mellitus

NOS,

Pancreatitis

necrotizing


Paroxetine 2,5,6,7,8,9,

Valproate 1,7,8,9

U Peak glucoseunknown. Concomitant medications

were begun concurrently with olanzapinc. Status of

olanzapineand concomitantuse, when necrotizingpancrcatitis was found I month after diabetes was

diagnosed, is unknown; it is unknown if patient

hospitalized or ifautopsyperformed. From reported

data, it is possible olanzapine, paroxetineand valproate

were beingadministeredwhen necrotizing pancreatitis

began.

24 29.07 US000744983 Death NOS,Dizziness cxc

vertigo,

Hyperglycaemia

NOS,

Vomiting NOS

OE U Quetiapine2,7,8 U Peak glucose 175 mg/dL. Risk factors wererace andalcoholismhistory. This case lacked clinical data

necessary for precise assessment. Non-fastingglucose

had been 175 mg/dl without concurrent DKAon

olanzapine approximately 10 months prior to reported

DKA. The acute terminal episode of nausea and

vomiting while on only quctiapinemay have causedor

beenthe consequenceof ketoacidosis, or, have

originated witha primary gastrointestinal process.

Patientsreported terminal diagnosis of diabetic

ketoacidosis' was made after he had been off

olanzapine for 23 daysand on quctiapinc for 11 days;

glucosereportedly was 175 mg/dl when diagnosed withDKA at terminal admission. Died at unknown interval

after admission due to unreported cause;unknown iftoxicology andautopsyperformed.

25 29.08 US000948765 Confusion,

Dyspnoea NOS,

Hyperglycaemia

NOS,

Lung cancerstage

unspecifiedcxc

metastatic tumoursto

lung,

Respiratory arrest

excneonatal

OE N Diclofenac7,8,

Insulin human injection

isophane

Y Peak glucose>800 mg/dl. Post-marketing studyparticipantwith exacerbationof diabetes mellitus2

monthsafter starting olan7.apine. Concurrent

metastatic lungcancer, probable hyperlipidemia,and

obesity are etiologies for exacerbation ofdiabetes

mellitus. Presented4 monthslater withdyspneaand

confusion attributed by investigatorto metastaticlung

cancer. Respiratoryarrestand death were reportedly

due to metastaticlung cancer; on olan7.apinc,

diclofenacand insulin at death.

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Table 3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported and the Patient Wason


pa

-

CaseID

26 1.54 US000948999

MedDRAPreferred

Terms

Etiology of

Glucose.

Dysregulation

Death

Reported as

Glucose

Metabolism

Related?

ConcomitantDrugs


withGlucose


Pancreatitis and/or. .

Weight Gain

ReportedPre

Existing

Glucose.

Dysregulation CommentsDiabeticketoacidosis POE Y U Y Peak glucose843 mg/dL post-mortem. Autopsy

revealedtriple vessel coronaryartery atherosclerosis,

macrovesicularsteatosis ofliver and perimortem

fracture of left 6th rib. Patient's diagnosis of

`borderline'diabetes mellitus was made only3 days

beforedeath. Post-mortemdiagnosisof ketoacidosis

withreportedvalue for acetoneof 0.029 W/V by gas

chromatography. Potassium of 16 meq/L from

unspecifiedsample. Post-mortembicarbonateof


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Table3.3. Category 1: Cases of Death in Which Glucose Dysregulationwas Reported and the Patient Was onOlanzapine at EventOnset n=48 continued

aBc.J Case ID

MedDRAPreferredTerms

Etiology of

Glucose.Dysregulation

Death

Reportedas

Glucose

Metabolism

Related?

Concomitant DrugsTemporallyAssociated

th Glucose

Dysregulation, Acidosis,Pancreatitisand/or

.Weight Gain

ReportedPre.

ExistingGlucose

.Dysregulation Comments

28 30.10 US010259319 Blood glucose

increased,

Loss of consciousness

NEC,

OverdoseNOS,

Pulmonaryembolism,

Thirst,

Urinaryfrequency


Lithium 2,8,9U Peak glucose 1300 mg/dL. Family history, obesity and

agewererisk factors. Presented at outpatientclinic

with complaintsof thirstand urinary frequencyof

unreporteddurations; evaluation for urinary tractinfectionnotreported. Treatmentinterventionnot

reportedas having occurred. Threedays after

presentingwith thirstand urinary frequency, patient

hospitalized in comaand died from pulmonaryembolus. Progressionofpresentingevents to comaand

deathdue to pulmonary embolism may have resultedfrom dehydration, stasis and/oracutecoagulopathy;unknownif autopsyperformed. Detailsabout

laboratory data otherthan a single glucosewerenot

reported.

29 30.11 US010361601 Bloodglucose

increased,

Body temperature

increased,

Cardiacarrest,Death NOS,

Dizziness cxc

vertigo,Fall,

Sepsis NOS

OE U U U Peakglucose2lOomgldL. Organismcausingsepsis

wasnotreported. Presentedwith dizziness, fell and hithead; diagnosed with sepsis with feverto 42.2C,hadcardiopulmonaryarrestand died on day of presentation.

Interpretedas havingprobablecoma in courseofevents. Cause ofdeath reported as unknown but

contributedto by sepsis, cardiac arrestand

hyperglycemia. Autopsy not performed.

30 30.12 US010361653 Blood glucose

increased,

DeathNOS

IN U U U Peak glucose220 mg/dL. Pastmedical and family

history,habitusand baseline laboratory values notreported. It was unknown if patient had prior episodes

ofhyperglycemiaor diabetes mellitus. Clinicaldetailssurroundingthe death werenotreported. Cause ofdeath not reported; unknown if autopsy performed.

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Table3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported and the Patient Was on

Olanzapine at EventOnset n=48 continued

ECase ID

MedDRA Preferred

Terms

Etiologyof

Glucose

Dsregulation

Death

Reportedas

Glucose

Metabolism

Related?

ConcomitantDrugs


withGlucose


Pancreatitis and/or

WeightGain

ReportedPre

Existing

Glucose


31 10.06 USO 10361657

32 18.07 US010362485

Death NOS,

Influenzalike illness,

Nonketotic

hyperglycaemic-

hyperosmolarcoma,

PneumoniaNOS,

Pulmonaryembolism,

Renal failure NOS,

Respiratory failure

exc neonatal,

Upper gastrointestinal

haemorrhage,

Weight increased

Death NOS,

Diabetesmellitus

NOS,

OverdoseNOS

OE

POE

N

U

Isoniazid 1 ,2

Ciprofioxacin 1,2,

Clonazepam 8,9,

Levothyroxine2,

Topiramate 1,2,5,6,7,8

U

U

Peak glucose2000 mg/dL. Risk factors were age, race,obesity, weight gain. After 11 months of olanzapine

use, 45-year-old patient with chronic obstructive

disease andunspecifiedpulmonaryproblems, living in

an extended care residence, developed acute flu-like

illness and hyperglycemia, hyperosmolarnon-ketotic

coma associated with pneumonia, respiratory and renal

failure; takingisoniazid. Death occurred reportedly

dueto probablepulmonary embolismandrespiratory

failure duringthe secondhospital admission,after

patient off olanzapine approximately 6 weeksand with

unknown status of concomitant use. Glucose

metabolism at the terminal admission not reported.

Peakglucose unknown. Concomitantuse of

ciprofloxacinfor unspecifiedinfectionat the timeof

diabetes mellitus diagnosis. Death - I m after glucose

dysregulation diagnosedand controlled by diet. Found

dead in bed at home. Autopsyrevealed coronary artery

disease and old myocardial infarction; cause ofdeath

notreported.

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OlanzapineLY170053 Glucose4 UpdateConfidential 26 March 2003

Table3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported a nd the Patient Was onOlanzapine at Event Onset n=48 continued

ECase ID

MedDRAPreferred

Terms

Etiology of

Glucose

Dsregu1ation

DeathReported asGlucose

Metabolism

Related?

Concomitant Drugs


with Glucose


Pancreatitis and/or

Weight Gain

Reported Pre

Existing

Glucose

Dsregu1ation Comments

33 1.65 USO 10564728 Chestpain NEC,Diabeticketoacidosis,Dizziness exc

vertigo,

Death

OE N Carbarnazepine2,5,7,Diltiazern2,9,

Diphenhydramine9,

Enalapril7,Fluoxetine 2,3,5,7,8,9,

Glipizide.

Hydroxyzine pamoate

2,9,

Insulin,

Torsernide 2

Y Peak glucose 461 mg/dL. Post-marketingstudyparticipant; pre-olanzapincType I diabetes mellitus,

obesity BMI 30.2kg/rn2, pulmonaryand systemic

hypertension, end-stageliverdisease, drug and alcoholabuse, severe noncompliancewith follow-up, andconcomitant medicationsare all risk factors.

Diagnosedwith diabetic ketoacidosis, HCO3 8 meq/L,

urine ketones 150 mgldl;pH not reported. Had coffeeground emesis, weakness, nausea and 11gb 7.4 g/dl;

DKAat that time reportedly due to alcohol abuseand

"gross' noncompliance. Hadchestpainand dizziness

after 3 daysofstudy drugolanzapine. Death reported

4monthsafter DKA, and was "natural." Patient had

been drinking heavily and possiblynoncompliant withmedieations. Autopsyrevealed cardiomegaly, right

ventricularhyperirophywith dysplasia on posterior

wall, hcpatic micronodularcirrhosis, splenomegaly,

intact gastroesophageal varices, nephrosclerosis,post

cholecystectomy and appendectomy. DKA improved

on 01 an zapineand insulin; unknown status ofolanzapineuseat time

ofdeath.34 1.66 USO 10565220 Death NOS,


Vision blurred,

Dry mouth

POE U Albuterol2,

Amitriptyline2,8,9,

Chlorpromazine 2,9,Clonidine2,9,

Fluoxetine 2,3,5,7,8,9

U Peak glucose 1600 mgldL. Autopsyresults and

toxicology not reported for legal reasons. Patient

taking methadone for polysubstanceabuse. Concurrent

diagnosesofasthma and hepatitis C; Presentedthe daybeforedeath with blurred visionand dry mouth,and

was diagnosedas havingan allergic reaction; glucose

levelnot reportedas performed. Dayofdeath

presented to ER with unreported symptoms, diagnosed

with DKA, transferred to ICU and died. Status of

medicationcompliancewas unknown. Medical

examiner was unableto providea copy ofautopsyor

other records.

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Table 3.3. Category 1: Casesof Death in Which Glucose Dysregulation was Reported and the Patient WasonOlanzapine at EventOnset n=48 continued

.

-j r CaseID

MedDRAPreferred

Terms

Etiologyof

Glucose

Dysregulation

Death

Reported as

Glucose

Metabolism

Related?

Concomitant Drugs


with Glucose

Dysrcgulation, Acidosis,

Pancreatitis and/or

Weight Gain

Reported Pre

Existing

Glucose


1.67 US010565235 Diabeticketoacidosis,Muscle twitching

IN Y Lithium 2,8,9 U Peak glucose610 mg/dl post-mortem; sample site notreported. Diagnosisofdiabetic ketoacidosis made

post-mortem. BMInot reported; weight 102.7 kg; race

only reportedrisk factor. Toxicologyconfirming

presence of olanzapineand concomitantlithium at the

time of deathnotreported. Two days before he died at

home, patient was seen in ER for hand twitching;

lithium level was`normal.' No otherlabs reported.

Case report ofprobablediabetic ketoacidosislacks

baseline glucose, habitus. personal and family medical

history, clinical contextofdeath, and, start datesor

durations ofolanzapincand lithium use.

3.01 USO10565250 Diabetesmellitus

NOS,

Ketosis

POE Y Lithium 2,8,9 U Peak glucose 1185 mg/dL post-mortem. Autopsyand

toxicology not reported for legal reasons. Found dead

athome. Diagnosisofhyperglycemiaand ketosisdue

to diabetes mellitus madepost-mortem. Site of

samplings vitreoushumor vs. bloodand post-mortem

intervalto sampling not reported. Toxicology,to

confirm thepresence ofolanzapine, lithium,and the

presenceor absenceofethanol, was not reported.

Patienthad history of alcohol dependence, cocaine

abuse, hypertensionand hepatitisC..70 US010768802 Diabetic ketoacidosis IN Y Lithium 2,8,9 U Peak glucose unknown. Nobaselinelaboratory values

were reported. Past medical and familyhistory, habitus

andclinical events surroundingthe death were not

reported. Developeddiabetic ketoacidosisand died; on

olanzapineand lithium at timeof death; cause ofdeath

diabetic ketoacidosis; unknown if autopsy was

performed.

2.28 US010769550 Death NOS,

Ketoacidosis

IN U U U Peak glucose800 mg/dL. Pastmedicalandfamily

history, and habitus notreported. Patient developed

ketoacidosisand died. Unknown if autopsyperformed.

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Table 3.3. Category 1: Cases of Death in Which Glucose Dysregulation was Reported andthe Patient Was on


CaseID

MedORA PreferredTerms

Etiology of

Glucose

Dysregulation

Death

Reportedas

Glucose

Metabolism

Related?

ConcomitantDrugs


with Glucose


Pancreatitis and/or

Weight Gain

Reported Pre

Existing

Glucose


39 12.11 USOI 0871705 Convulsions NOS,

Death NOS,

Diabeticcoma NOS,Hyperglycaemia

NOS

POE U Chloi-propamide Y Peak glucose488 mg/dL. Patient with pre-olanzapine

stable, controlled diabetes mellitustreatedwith oral

hypoglycemic agent, had a seizure, was foundto have

hyperglycemiaand reportedlya diabetic comaand

died. Cause ofdeathreportedas unknown. No

description of surrounding clinical events was

provided. Seizure etiology was not reported. Timing

of glucose measurementrelative to seizure was not

reported.

40 1.77 US010973861 Diabeticketoacidosis IN Y N U Peak glucose unknown. Past medical history, baseline

laboratory values, family historyand habitus notreported. Race was only reportedriskfactorfor

diabetes. Aftera several-year history of olanzapine

administration, patient apparently abruptly developed

diabeticketoacidosisand died within 24 hours

following hospital admission. Becauseofpaucity of

reported clinical data,the case cannot be assessed with

respect to causation ofDKA.

41 1.78 US010974040 Diabetic

hyperosniolarcoma,Diabeticketoacidosis,

Renal failure NOS,Metabolic acidosis,ConvulsionsNOS,

Tonsillitisacute

NOS,

Hyponatremia,

Hyperuricemia,

C-reactive protein

increased,

Hypokalemia,

Blood creatinineincreased

OE Y Flunitrazepani 8,9,

Risperidone3,8,

Triazolam8,9,

Mefenamicacid 2,7,8,9,Hydrocortisone 2,9

Y Peak glucose 1655 mg/dl. Pre-olanzapine glucoseof

80mg/dl was measuredapproximately 20 months

before startingolanzapine, and, priorto treatment with

risperidone. Patient with risk factors of race, obesity, astronglypositive family history for diabetes had knowndiabetes mellitus before infectious prodrome of

pharyngitisbegan. Infectiouspharyngitis exacerbated

diabetes thatappearsnot to havebeen treated with

hypoglycemicagents at hospital admission when

glucosewas 600 mgldl. Intravenous glucose,

antibiotics, hydrocortisoneand large volumeof juice

were followedby peak glucose, hyperglycemic coma,

electrolyte imbalance, pH 7.25 and death. Cause ofdeath reported to be hyperglycemia, diabetic comaanddehydration.

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Table33. Category 1: Cases of Death in Which Glucose Dysregulationwas Reportedand the Patient Was onOlanzapine at Event Onset n=48 continued

`

CaseII

MedDRAPreferred

Terms

Etiologyof

Glucose

Dysregulation

Death

Reportedas

Glucose

Metabolism

Related?

ConcomitantDrugs


withGlucose


Pancreatitis and/or

Weight Gain

ReportedPre

Existing

Glucose


42 2.30 USO11075155

-

Ketoacidosis IN Y Carbamazepine 2,5,7,

Paroxetine hydrochloride

2,5,6,7,8,9

U Peak glucose unknown. Past medical history, weight,

habitus,and family history not reported; duration of

olanzapineuse, baseline glucose and HbAlc not

reported. Race was a risk factor for diabetes mellitus.

Reportedly developed slight elevation of post-prandial

bloodglucose levels following initiation of olanzapine,

butno valuesreported, and no treatment of

hyperglycemiareported. Patientdied following

ingestion of `a lot ofcandy" and before seeing

physician. Cause ofdeathreportedas secondary to

ketoacidosis; glucose, pH, ketones, and bicarbonate

levels not reported. Unknown if autopsy was

performed.

43 13.02 USOI 1075562 Cardiac arrest,

ConvulsionsNOS,

Diabetesmellitus

insulin-dependent,

Lung infiltration

NOS,Pyrexia,

Ventricular

fibrillation

POE N N U Peak glucose >1000 mg/dl. Past medical history

reportedly negative for diabetes mellitus, cardiac

problems or seizures;unknown regarding prior

hyperglycemia. Risk factors includefamily history of

diabetes. Reported as not on any concomitant

medications; weight, habitus not reported. No baseline

laboratoryvalues reported. Hospitalized for seizures

aftertaking olanzapine 5 years. Hyperglycemia

occurredin context of seizures, fever, pneumoniawithsubsequent sepsis during hospitalization. Concurrent

pulmonary infiltrates, cardiomyopathy EF 30% by

echocardiogram, positiveCIA antibody, elevated

glycosylated hemoglobin no valuereported;

developedbacteremia from enterobacter; treated with

levofloxacin, ceftriaxone, insulin, ramipril, metoprolol,

diuretics, aspirin. Olanzapine held for 6 days; restarted

2days prior to ventricular fibrillationand cardiac

arrest. Unknown if autopsyperformed. Cause ofdeath

reportedas ventricular fibrillationand cardiac arrest.

Pneumonicinfiltratesand cardiomyopathy etiologies

not specified.

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